Investigation of the structural requirements for the kappa-selective opioid receptor antagonist, 6 beta,6 beta'-[ethylenebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)- 4,5 alpha-epoxymorphinan-3,14-diol] (TENA).
Investigation of the structural requirements for the kappa-selective opioid receptor antagonist, 6 beta,6 beta'-[ethylenebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)- 4,5 alpha-epoxymorphinan-3,14-diol] (TENA).
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DOI：
10.1021/jm00155a048
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发表时间：
1986-05
影响因子：
7.3
通讯作者：
S. Botros;A. Lipkowski;A. Takemori;P. Portoghese
中科院分区：
文献类型：
--
作者：
S. Botros;A. Lipkowski;A. Takemori;P. Portoghese
In an effort to determine whether or not the basic nitrogens in the spacer of the bivalent ligand 6 beta,6 beta'-[ethylenebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)4,5 alpha-epoxymorphinan-3,14-diol] (TENA, 1) is responsible for its selective kappa opioid antagonist activity, we have synthesized monovalent analogues 2-4 that contain a C-6 side chain with basic nitrogens. Analogue 2 behaved as a potent opioid agonist in the guinea pig ileum preparation (GPI) and possessed no significant kappa opioid antagonist activity (IC50 ratio = 1) relative to TENA (IC50 ratio = 20). The agonist activity of 3 and 4 interfered with the opioid antagonist assay and therefore did not permit evaluation of antagonist activity in a concentration range where TENA is effective. Although the results obtained with 2 are consistent with the requirement of a second opiate pharmacophore (rather than a second basic nitrogen in the spacer) for the kappa antagonist activity of TENA, the potent agonism associated with these monomers do not allow a firm conclusion in this regard.
